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TGF-ß Signaling Pathway and Colorectal Cancer

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Molecular Pathogenesis of Colorectal Cancer

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Abstract

The Transforming Growth Factor Beta (TGF-ß) signaling pathway is one of the most commonly disrupted pathways in colorectal cancer. Its deregulation appears to mediate cancer formation through a variety of mechanisms. TGF-ß is the canonical member of a family of secreted proteins that include the TGF-ß isoforms, TGF-ß1, TGF-ß2, and TGF-ß3; activins; Growth and Differentiation Factors (GDFs); bone morphogenetic proteins (BMP); inhibin, nodal, and anti-Mullerian hormone. These ligands all mediate biological activities in cells through binding to cell surface receptor complexes that are composed of type I and type II heteromeric receptors. In the colon, TGF-ß can inhibit cell proliferation, induce apoptosis, and induce terminal differentiation, which suggests this pathway has tumor suppressor activities in colorectal cancers. This role of a tumor suppressor pathway is supported by the identification of inactivating mutations and epigenetic alterations in many TGF-ß pathway genes, including TGFBR2, SMAD4, SMAD2, BMPR2A, and ACVR2. Interestingly, some studies have suggested that in certain contexts TGF-ß may promote the invasive or metastatic behavior of established cancer cells suggesting TGF-ß has a paradoxical role in primary human cancers that appears to depend on the stage of cancer. This chapter will focus on the tumor suppressor activity of the TGF-ß signaling pathway in colorectal cancer and will highlight mechanisms through which TGF-ß signaling mediates its antitumor effects.

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Abbreviations

MMP:

Matrix metalloprotease 2

MMP9:

Matrix metalloprotease 9

TSP1:

Thrombospondin 1

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Acknowledgements

Support for these studies was provided by the NIH (RO1CA115513, P30CA15704, UO1CA152756, and 5P01CA077852), and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG).

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  1. Fred Hutchinson Cancer Research Center, University of Washington Medical School, 1100 Fairview Avenue North, D4-100, Seattle, WA, 98109, USA

    William M. Grady

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    Kevin M. Haigis, Ph.D.

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Grady, W.M. (2013). TGF-ß Signaling Pathway and Colorectal Cancer. In: Haigis, Ph.D., K. (eds) Molecular Pathogenesis of Colorectal Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8412-7_7

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